May 2009

Treating Fibromyalgia
Antidepressants offer some relief for sufferers of fibromyalgia.

Donepezil in Schizophrenia?
A recent report suggests donepezil (Aricept) does not appear to benefit cognitive symptoms of schizophrenia.

Second-Generation Antipsychotics and the Risk of Cardiac Death
Second-generation antipsychotics produce about the same level of cardiac risks as first-generation agents.

Preventing Dementia
Higher levels of education, mentally challenging work, and moderate coffee consumption may protect against Alzheimer’s disease, but Ginkgo biloba does not.

In Brief
Mixed Results for Modafinil as an Adjunct in Schizophrenia; Memantine Not Efficacious as an Adjunct in Schizophrenia

Preventing Dementia

May 2009

Alzheimer’s disease is growing in prevalence and devastating in consequences. How can we protect ourselves against its ravages? Higher levels of education, mentally challenging work, and moderate coffee consumption appear effective, but Ginkgo biloba does not.

The bad news first. DeKosky and coworkers observe that worldwide sales of ginkgo exceed $249 million annually.1 In some countries, ginkgo is believed to preserve memory. It has antioxidant properties, which might delay the pathological changes that can cause dementia and cerebrovascular disease, and it may also have anti-amyloid aggregation effects.

Studies of ginkgo to attenuate or prevent dementia have yielded mixed results. The largest and longest randomized controlled trial to date enrolled 3069 community volunteers, aged 75 years or older, at five academic medical centers. Subjects had normal cognition or mild cognitive impairment at study entry. In double-blind fashion, patients were randomly assigned to take ginkgo, 120 mg bid, or placebo. They were assessed every 6 months for the development of dementia and followed for a median of 6.1 years.

Dementia developed in 523 participants—246 taking placebo and 277 receiving ginkgo. Of the dementia cases, 92% were classified as possible or probable Alzheimer’s disease or Alzheimer’s disease with evidence of vascular brain disease. Ginkgo had no effect on the rate of progression to dementia in patients with mild cognitive impairment. Adverse effect profiles were similar in both groups, with no statistically significant differences.

In an accompanying editorial, Schneider points out that the hazard ratios numerically favored placebo over ginkgo.2 Ginkgo also lacked positive effects in reducing serious cardiovascular adverse events or total mortality. The 25% of participants who entered the study with cardiovascular disease actually showed an increased risk for developing dementia when they were taking ginkgo as opposed to placebo. Hemorrhagic stroke was infrequent but more likely in patients taking ginkgo.

Schneider notes a 2007 Cochrane systematic review that found no convincing evidence of clinically significant benefit from ginkgo for people with dementia or cognitive impairment.3 As opposed to the DeKosky study, the Cochrane review focused on short-term trials of 6 to 26 weeks. In addition, the German manufacturer conducted a regulatory trial that failed to demonstrate efficacy. Also, Canter and Ernst, in a 48-month study of 122 cognitively normal people, 85 years or older, found that ginkgo was no better than placebo.4 A secondary analysis controlling for medication adherence did show some benefit for ginkgo, but subjects taking ginkgo suffered more strokes (n = 6) and transient ischemic attacks (n = 1) than those receiving placebo (n = 0) (P = .01).

More positive results come from a study of education and work by Girabotto et al.5 They tested memory and cognitive skills in 242 people with Alzheimer’s disease, 72 with mild cognitive impairment, and 144 control subjects. They also measured brain glucose metabolism to assess the extent of pathological changes from Alzheimer’s disease. Among patients with Alzheimer’s disease or mild cognitive impairment that progressed to Alzheimer’s disease during the course of the study, those with less mentally taxing jobs and less education had more memory impairment for a given level of Alzheimer’s-related tissue damage. There was no such association in the healthy controls or those who began with mild cognitive impairment but did not develop Alzheimer’s disease.

Many studies have suggested that coffee protects against Alzheimer’s disease and other forms of dementia. Although it also contains caffeine, there is little evidence that tea has this benefit. Eskelinen and coworkers in Finland studied how coffee and tea drinking at midlife might influence the later development of dementia.6

The authors assessed over 1400 people, aged 65 to 79 years, after an average follow-up of 21 years. At midlife, 46% drank three to five cups of coffee per day (moderate) and 39%, more than five cups daily (high). A minority drank tea, usually only one to two cups per day.

Moderate coffee drinkers had a 65% to 70% decreased risk of dementia and a 62% to 64% decreased risk of Alzheimer’s disease compared with those who were low coffee consumers (zero to two cups per day). High coffee consumers also had a decreased dementia risk, but not as much as in the moderate group. The benefits of coffee drinking held even when analyses were adjusted for demographic, lifestyle, and vascular factors; apolipoprotein E ⏖ allele status; and depressive symptoms. Tea drinking did not appear to affect the risk of dementia, but the number of tea drinkers was so small that the authors caution about drawing a conclusion.

Coffee’s benefit could come from magnesium, which increases insulin sensitivity; stimulation of cholinergic neurons; or the neuroprotective or antioxidant capacity of caffeine. The authors hope for further research to confirm these observations.

As the population ages, dementia will become a bigger and bigger public health problem. Ginkgo biloba does not appear to be a preventative. On the positive side, healthy diet, exercise, moderate coffee consumption, and mental challenges and stimulation appear to be beneficial.

1DeKosky ST, Willimson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL, Furberg CD; Ginkgo Evaluation of Memory (GEM) Study Investigators: Ginkgo biloba for prevention of dementia: A randomized controlled trial. JAMA 2008;300:2253-2262.

2Schneider LS: Ginkgo biloba extract and preventing Alzheimer disease. JAMA 2008;300:2306-2308.

3Birks J, Grimley Evans J: Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2007;(2):CD003120. doi:10.1002/14651858.CD003120.pub2.

4Canter PH, Ernst E: Ginkgo biloba is not a smart drug: An updated systematic review of randomised clinical trials testing the nootropic effects of G. biloba extracts in healthy people. Hum Psychopharmacol 2007;22:265-278.

5Garibotto V, Borroni B, Kalbe E, Herholz K, Salmon E, Holtoff V, Sorbi S, Cappa SF, Padovani A, Fazio F, Perani D: Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology 2008;71:1342-1349.

6Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M: Midlife coffee and tea drinking and the risk of late-life dementia: A population-based CAIDE study. J Alzheimers Dis 2009;16:85-91.